One major health concern for the elderly population is age-related hearing loss (presbycusis), which is consistently associated with age-related loss of hair cells and spiral ganglion neurons (SGNs). The sequence of causative molecular events for age-related loss of SGNs is unknown. Certain nicotinic acetylcholine receptors (nAChRs) are highly expressed in SGNs. Recently, nAChRs were found to contribute to age-related neuronal degeneration in the central nervous system, and it is unknown whether nACHRs also contribute to age-related loss of neurons in the peripheral nervous system. Preliminary works have revealed: (a) alterations of the expression level of alpha 4, alpha 5, and beta 2 nAChR subunits in SGNs during aging; and (b) an accelerated age-related hearing loss and correspondent loss of SGNs in mice lacking the beta 2 subunit, but not in mice lacking the alpha 5 subunit. This application focuses on possible roles nAChRs may have on age-related loss of SGNs. The general hypothesis is that certain nAChR subunits play an essential role in age-related loss of SGNs. The two specific Aims are: (a) to determine the temporal profile of nAChRs expression during age-related SGN loss, and (b) to assess how direct manipulation of nAChRs in vivo influences age-related loss of SGNs. This application introduces a powerful new approach, the conditional tissue-specific transgenic method, to directly test possible involvements of nAChRs in the age-related loss of SGNS. The ultimate goal of this research is to develop methods for prevention and treatment of age-related loss of SGNs, based on identifying molecular candidates involved in this aging process.